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Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Salazar-Mather TP, Orange JS, Biron CA - J. Exp. Med. (1998)

Bottom Line: Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses.NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers.The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

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Related in: MedlinePlus

Demonstration and characterization of MCMV-induced leukocyte cell trafficking to livers. Bone marrow leukocytes were harvested from  uninfected untreated or uninfected antibody-treated mice and labeled with the fluorescent dye, PKH26. Labeled cells were transferred intravenously to  recipient mice that were either uninfected or infected with MCMV for 24 h. Livers were harvested 24 h after cell transfer, processed, sectioned, and examined by fluorescence microscopy as described in Materials and Methods. All panels present area encompassing a central vein. (cv, central vein, given in  A for orientation). Sections of livers isolated from the following recipient mice are shown: (A) uninfected C57BL/6 recipient after transfer of cells from  untreated C57BL/6 donor mice, (B) MCMV-infected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (C) uninfected  C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (D) infected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (E) infected C57BL/6-SCID recipient after transfer of cells from anti-F4/80 antibody-treated C57BL/6-SCID donor mice, (F) infected C57BL/6-SCID recipient after transfer of cells from anti-NK1.1 antibody-treated C57BL/6-SCID donor mice, (G) uninfected C57BL/6 recipient after transfer of cells from untreated E26 mice, and (H) infected C57BL/6 recipient after transfer of cells  from untreated E26 mice. Large arrows point to “hot spots” with cell clusters between the portal area and central vein. Small arrows point to individual  elongated cells in hepatic sinusoids. Photographs were taken at ×31.25. Bar, 100 μm.
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Figure 2: Demonstration and characterization of MCMV-induced leukocyte cell trafficking to livers. Bone marrow leukocytes were harvested from uninfected untreated or uninfected antibody-treated mice and labeled with the fluorescent dye, PKH26. Labeled cells were transferred intravenously to recipient mice that were either uninfected or infected with MCMV for 24 h. Livers were harvested 24 h after cell transfer, processed, sectioned, and examined by fluorescence microscopy as described in Materials and Methods. All panels present area encompassing a central vein. (cv, central vein, given in A for orientation). Sections of livers isolated from the following recipient mice are shown: (A) uninfected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (B) MCMV-infected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (C) uninfected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (D) infected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (E) infected C57BL/6-SCID recipient after transfer of cells from anti-F4/80 antibody-treated C57BL/6-SCID donor mice, (F) infected C57BL/6-SCID recipient after transfer of cells from anti-NK1.1 antibody-treated C57BL/6-SCID donor mice, (G) uninfected C57BL/6 recipient after transfer of cells from untreated E26 mice, and (H) infected C57BL/6 recipient after transfer of cells from untreated E26 mice. Large arrows point to “hot spots” with cell clusters between the portal area and central vein. Small arrows point to individual elongated cells in hepatic sinusoids. Photographs were taken at ×31.25. Bar, 100 μm.

Mentions: To evaluate and characterize virus-induced cell trafficking to liver, cells were prepared, stained with the red fluorescent lipophilic dye, PKH26, and transferred by intravenous injection into recipient uninfected and MCMV-infected mice. Based on our previous studies examining virus-induced changes in bone marrow cellularity and cell trafficking to spleens (34), bone marrow populations isolated from uninfected mice were used for cell transfers. Fluorescently labeled cells for analysis were isolated from untreated donor C57BL/6 or T and B cell–deficient C57BL/6-SCID mice, and transferred into genetically matched uninfected or 24-h MCMV-infected recipient mice. Livers were harvested at 24 h after cell transfer, i.e., day 2 after MCMV infection. Samples were sectioned, and analyzed by fluorescent microscopy. Donor-derived cells were evident in sinusoidal cavities surrounding hepatocytes in both uninfected and infected mice (Fig. 2, A–D). These cells exhibited elongated cytoplasmic processes. Although migration to these areas was observed in uninfected mice, it was modestly induced in infected mice. In addition to this sinusoidal cell migration pattern, an intense donor cell trafficking to focal aggregates was observed in MCMV-infected, but not in uninfected, recipient mice (Fig. 2, B compared to A, and D compared to C). In similarity to the inflammatory foci identified by H&E, majorities of these clustered cells, or “hot spots,” were found between portal areas and central veins, and averages of four to six foci, with >5 cells/foci, were observed per hepatic lobule. Comparison of migration patterns with donor cell populations isolated from normal and T and B cell–deficient mice (Fig. 2, A and B compared to C and D) demonstrated that both the sinusoidal localizations and focal aggregations were T and B cell independent. Moreover, as both patterns were observed in T and B cell–deficient recipient mice, their induction also was independent of these cell types. The results demonstrate a dynamic cell migration to sinusoidal cavities in uninfected and infected mice, and a virus-induced unique cell cluster migration with characteristics of inflammatory foci.


Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Salazar-Mather TP, Orange JS, Biron CA - J. Exp. Med. (1998)

Demonstration and characterization of MCMV-induced leukocyte cell trafficking to livers. Bone marrow leukocytes were harvested from  uninfected untreated or uninfected antibody-treated mice and labeled with the fluorescent dye, PKH26. Labeled cells were transferred intravenously to  recipient mice that were either uninfected or infected with MCMV for 24 h. Livers were harvested 24 h after cell transfer, processed, sectioned, and examined by fluorescence microscopy as described in Materials and Methods. All panels present area encompassing a central vein. (cv, central vein, given in  A for orientation). Sections of livers isolated from the following recipient mice are shown: (A) uninfected C57BL/6 recipient after transfer of cells from  untreated C57BL/6 donor mice, (B) MCMV-infected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (C) uninfected  C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (D) infected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (E) infected C57BL/6-SCID recipient after transfer of cells from anti-F4/80 antibody-treated C57BL/6-SCID donor mice, (F) infected C57BL/6-SCID recipient after transfer of cells from anti-NK1.1 antibody-treated C57BL/6-SCID donor mice, (G) uninfected C57BL/6 recipient after transfer of cells from untreated E26 mice, and (H) infected C57BL/6 recipient after transfer of cells  from untreated E26 mice. Large arrows point to “hot spots” with cell clusters between the portal area and central vein. Small arrows point to individual  elongated cells in hepatic sinusoids. Photographs were taken at ×31.25. Bar, 100 μm.
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Related In: Results  -  Collection

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Figure 2: Demonstration and characterization of MCMV-induced leukocyte cell trafficking to livers. Bone marrow leukocytes were harvested from uninfected untreated or uninfected antibody-treated mice and labeled with the fluorescent dye, PKH26. Labeled cells were transferred intravenously to recipient mice that were either uninfected or infected with MCMV for 24 h. Livers were harvested 24 h after cell transfer, processed, sectioned, and examined by fluorescence microscopy as described in Materials and Methods. All panels present area encompassing a central vein. (cv, central vein, given in A for orientation). Sections of livers isolated from the following recipient mice are shown: (A) uninfected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (B) MCMV-infected C57BL/6 recipient after transfer of cells from untreated C57BL/6 donor mice, (C) uninfected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (D) infected C57BL/6-SCID recipient after transfer of cells from control-IgG-treated C57BL/6-SCID donor mice, (E) infected C57BL/6-SCID recipient after transfer of cells from anti-F4/80 antibody-treated C57BL/6-SCID donor mice, (F) infected C57BL/6-SCID recipient after transfer of cells from anti-NK1.1 antibody-treated C57BL/6-SCID donor mice, (G) uninfected C57BL/6 recipient after transfer of cells from untreated E26 mice, and (H) infected C57BL/6 recipient after transfer of cells from untreated E26 mice. Large arrows point to “hot spots” with cell clusters between the portal area and central vein. Small arrows point to individual elongated cells in hepatic sinusoids. Photographs were taken at ×31.25. Bar, 100 μm.
Mentions: To evaluate and characterize virus-induced cell trafficking to liver, cells were prepared, stained with the red fluorescent lipophilic dye, PKH26, and transferred by intravenous injection into recipient uninfected and MCMV-infected mice. Based on our previous studies examining virus-induced changes in bone marrow cellularity and cell trafficking to spleens (34), bone marrow populations isolated from uninfected mice were used for cell transfers. Fluorescently labeled cells for analysis were isolated from untreated donor C57BL/6 or T and B cell–deficient C57BL/6-SCID mice, and transferred into genetically matched uninfected or 24-h MCMV-infected recipient mice. Livers were harvested at 24 h after cell transfer, i.e., day 2 after MCMV infection. Samples were sectioned, and analyzed by fluorescent microscopy. Donor-derived cells were evident in sinusoidal cavities surrounding hepatocytes in both uninfected and infected mice (Fig. 2, A–D). These cells exhibited elongated cytoplasmic processes. Although migration to these areas was observed in uninfected mice, it was modestly induced in infected mice. In addition to this sinusoidal cell migration pattern, an intense donor cell trafficking to focal aggregates was observed in MCMV-infected, but not in uninfected, recipient mice (Fig. 2, B compared to A, and D compared to C). In similarity to the inflammatory foci identified by H&E, majorities of these clustered cells, or “hot spots,” were found between portal areas and central veins, and averages of four to six foci, with >5 cells/foci, were observed per hepatic lobule. Comparison of migration patterns with donor cell populations isolated from normal and T and B cell–deficient mice (Fig. 2, A and B compared to C and D) demonstrated that both the sinusoidal localizations and focal aggregations were T and B cell independent. Moreover, as both patterns were observed in T and B cell–deficient recipient mice, their induction also was independent of these cell types. The results demonstrate a dynamic cell migration to sinusoidal cavities in uninfected and infected mice, and a virus-induced unique cell cluster migration with characteristics of inflammatory foci.

Bottom Line: Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses.NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers.The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

Show MeSH
Related in: MedlinePlus